Advanced endometrial cancer is a lethal disease from which over 7,000 women died in the year 2000. No novel treatment regimens have become available in many years. The growth of endometrial cancer is controlled by complex interactions between the steroid hormones estrogen and progesterone and growth factors, particularly the epidermal growth factor (EGF). The development of new molecules to block the EGF receptor (EGFR) has now provided an opportunity to test such agents in patients with advanced endometrial cancers who have failed standard therapy. In response to an invitation from the National Cancer Institute (CTEP), we have designed a cooperative phase II trial of the drug ZD1839 (Iressa) to be carried out under the auspices of the Gynecologic Oncology Group (GOG). In conjunction with the clinical trial, translational and basic investigations will be performed. The following Specific Aims are proposed. (1) We will carry out a phase II open-label trial evaluating the efficacy and safety of ZD1839 in approximately 56 patients with advanced or recurrent endometrial cancer. The principal hypothesis tested is that ZD1839 will significantly increase the number of patients with advanced endometrial cancer who are alive and progression-free at six months. (2) We will determine the effects of ZD1839 on biological correlates that comprise secondary endpoints for the trial. These include EGFR, phosphorylated EGFR, estrogen receptors (ER), and progesterone receptors (PR) in pre- and post treatment tissue biopsies, as well as the levels of ZD1839, ZD1839 activity, and soluble EGFR in serum samples. ZD1839 activity will be approximated by an ex vivo phosphorylation assay. We will test the hypotheses that ZD1839 blocks EGFR phosphorylation and that EGFR results in the down regulation of ER and PR that are preserved with ZD1839 treatment. The possible link between the activation of the MAP kinase pathway by EGF and the loss of hormone receptors in endometrial cancer is a novel focus of this proposal. (3) We will evaluate the effects of EGF and ZD1839 on proliferation, signaling, gene expression, reporter gene activation, and apoptosis in endometrial cancer cell lines. The ability of ZD1839 to further sensitize the cells to the growth limiting effects of paclitaxel and progesterone will be investigated. The goal of these studies is to evaluate a new medication for the treatment of endometrial cancer, investigate its action and potential synergy with other therapies in the laboratory, and generate data that may improve therapy in the future.